Abstract
The brain encodes and stores information about peripheral inflammation and can directly recapitulate prior inflammatory responses. However, whether individual cytokines activate specific neural circuits to produce distinct physiological responses remains unknown. To address this fundamental question, we mapped brain-wide responses to IL-1β and found prominent engagement of the bed nucleus of the stria terminalis (BNST). Using targeted recombination in active populations, snRNA sequencing, and circuit tracing, we discovered that corticotropin-releasing hormone-expressing BNST neurons encode IL-1β signals. Chemogenetic reactivation of these neurons precisely recapitulates the physiological signatures of IL-1β exposure with increased circulating IL-6 and corticosterone and tachycardia. These responses require a defined BNST→paraventricular nucleus→rostral ventrolateral medulla→β receptor adrenergic signaling pathway. Critically, restraint stress also activates these BNST IL-1β-encoding neurons to generate the same physiological responses. Our findings establish how a single inflammatory mediator uses a precise neural circuit to activate systemic responses and provide mechanistic insight into the neuroimmune interactions underlying stress-related psychiatric and inflammatory diseases.